Why Me? Understanding the Causes of Diabetes
The roles of genes and the toll of the environment
It is the question that almost everyone with a serious illness asks at some point: Why me? What did I do to deserve this? Was it my fault? Or is someone else to blame?
When it comes to diabetes, there's no real answer yet. Yes, science has begun to uncover the roots of this disease, unearthing a complex interplay of genes and environment—and a lot more unanswered questions. Meanwhile, there's plenty of misinformation to go around. (How often have you had to explain that diabetes doesn't happen because someone "ate too much"?)
Both type 1 and type 2 diabetes are on the rise, with an estimated 24 million cases in the United States and 220 million worldwide. Understanding the causes of diabetes may stem its growth and help those already living with the disease day after day.
The Role of Genes
If genetics has taught us anything about diabetes, it's that, for most people, genes aren't the whole story. True, a few rare kinds of diabetes—including those collectively called MODY for maturity-onset diabetes of the young—have been traced to defects in a single gene. But for other types of diabetes, hereditary factors are still not well understood.
Scientists have done studies of twins to help estimate how important genes are in determining one's risk of developing diabetes. Identical twins have identical genes and thus the same genetic risk for a disease. Research has found that if one identical twin has type 1 diabetes, the chance that the other twin will get the disease is roughly 40 or 50 percent. For type 2 diabetes, that risk goes up to about 80 or 90 percent. This might suggest that genes play a bigger role in type 2 than in type 1, but that isn't necessarily so. Type 2 is far more common in the general population than type 1, which means that regardless of genetics both twins are more likely to develop type 2 diabetes.
Over recent decades, and particularly in the past five years, researchers have found dozens of genes with links to diabetes. The count stands at about 50 genes for type 1 and 38 for type 2. The numbers have risen quickly in recent years because of advances in the gene-sequencing technology used to conduct genome-wide association studies. This technique involves taking the genetic compositions of a group of people with a disease and comparing them en masse to the genomes of people who don't have the disease.
Although there are dozens of known type 1 genes, about half of the risk attributable to heredity comes from a handful that coordinate a part of the immune system called HLA, which helps the body recognize nefarious foreign invaders, such as viruses, bacteria, and parasites. Type 1 diabetes is an autoimmune disease, in which the body's own immune system destroys the cells in the pancreas that produce insulin, so perhaps it is no surprise that immunity genes are involved. Other autoimmune diseases share the HLA gene link, which may be why people with type 1 are more likely to develop additional autoimmune disorders.
It's not as clear what the rest of the type 1 genes are up to, but researchers are eager to find out. "Even though something accounts for a small part [of the genetic risk], it could have a significant impact," says Stephen Rich, PhD, director of the Center for Public Health Genomics at the University of Virginia School of Medicine. Understanding these genes' role may clue researchers in to less obvious biological pathways involved in type 1 diabetes, and to possible prevention strategies.
A 2009 study shows how genetic information may shed light on the environment-gene interactions that lead to type 1. In the study, researchers found that one of the type 1 genes mediates the immune system's response to viruses. This finding supported the longtime hypothesis that a virus may somehow make the immune system attack the insulin-producing cells in the pancreas in people who are genetically susceptible to developing diabetes.
While many experts believe that most type 1 genes have been identified, the situation with type 2 diabetes is much different. A recent study found that the known genetic links to type 2 probably account for only about 6 percent of the genetic predisposition for that form of diabetes. This could mean either that some of the genes discovered have a bigger effect than is currently believed or that "we are still missing 94 percent of the genes," says Atul Butte, MD, PhD, an assistant professor of pediatrics at Stanford University.
The genes identified so far in people with type 2 include many that affect the insulin-producing beta cells of the pancreas, says Craig Hanis, PhD, a professor at the Human Genetics Center at the University of Texas Health Science Center in Houston. And yet he emphasizes that why people get type 2 isn't at all clear yet: "What it tells us is that diabetes is a complicated disease."
The good news is that behavior still seems to help shape whether someone with the genetic disposition actually develops type 2—and that changes in diet and exercise can sometimes be enough to ward off the disease. "People sometimes have the misconception that if we say something is genetic, then they can't do anything about preventing diabetes and its complications," says Hanis. But he notes that in a landmark study, lifestyle interventions prevented or delayed type 2 in nearly 60 percent of people at high risk. "If we focus on changing the environment, we can prevent diabetes," he says. "As we understand the genetics, we can prevent more of it."
The Toll of the Environment
Being too heavy gets the bulk of the blame for triggering type 2 diabetes. According to the National Institutes of Health, about 85 percent of people with type 2 diabetes are overweight or obese. But consider that the remaining 15 percent are not. Consider, too, that roughly two-thirds of overweight people and a third of those who are obese will never develop diabetes. In other words, normal-weight and thin people also develop type 2, while heavy people won't necessarily. Clearly, there is more to the connection between lifestyle and type 2 diabetes than just body size.
Before blood glucose levels rise, the body of a person destined for type 2 becomes resistant to insulin, much as bacteria can become resistant to antibiotics. Insulin is the signal for the muscles, fat, and liver to absorb glucose from the blood. As the body becomes resistant to insulin, the beta cells in the pancreas must pump out more of the hormone to compensate. People with beta cells that can't keep up with insulin resistance develop the high blood glucose of type 2 diabetes.
While there are competing explanations of the link between obesity and type 2 diabetes, Gerald Shulman, MD, PhD, a professor of internal medicine and physiology at Yale University, believes the key is figuring out insulin resistance. He has studied the causes of insulin resistance for 25 years and thinks he may have the answer to the weight-diabetes link.
What his theory boils down to is that type 2 diabetes is caused not by extra fat alone, but by fat stored in the wrong places. "Virtually all the individuals [with insulin resistance] have fat accumulation in liver and muscle," Shulman says, where it may disrupt normal biological processes, leading to insulin resistance. "If you can understand this, you can ideally come up with new ways to prevent insulin resistance and type 2 diabetes."
Supporting evidence for Shulman's theory comes from observations about a rare genetic illness called lipodystrophy. People with lipodystrophy can't make fat tissue, which is where fat should properly be stored. These thin people also develop severe insulin resistance and type 2 diabetes. "They have fat stored in places it doesn't belong," like the liver and muscles, says Shulman. "When we treat them . . . we melt the fat away, reversing insulin resistance and type 2 diabetes." Shulman's theory also suggests why some people who carry extra fat don't get type 2. "There are some individuals who store fat [under the skin] who have relatively normal insulin sensitivity, a so-called fit fat individual," he says. Because of the way their bodies store fat, he believes, they don't get diabetes.
So what determines where fat is stored, and thus a person's propensity for insulin resistance and type 2 diabetes? Well, just having more fat in the body increases the risk that some of it will get misplaced. But exercise may also have a role in fat placement. Exercise is known to reduce insulin resistance; one way it may do this is by burning fat out of the muscle. Because of this, getting enough exercise may stave off type 2 in some cases. Genes may also help orchestrate the distribution of fat in the body, which illustrates how lifestyle and genetics interact.
The beta cells may be another place where gene-environment interactions come into play, as suggested by the previously mentioned studies that link beta cell genes with type 2. "Only a fraction of people with insulin resistance go on to develop type 2 diabetes," says Shulman. If beta cells can produce enough insulin to overcome insulin resistance, a factor that may be genetically predetermined, then a person can stay free of diabetes. But if the beta cells don't have good genes propping them up, then diabetes is the more likely outcome in a person with substantial insulin resistance.
Beta cells are vulnerable to more than just bad genes, which may explain the associations between type 2 diabetes and environmental factors that aren't related to how much fat a body has or where it is stored. Beta cells carry vitamin D receptors on their surface, and people with vitamin D deficiency are at increased risk for type 2. Plus, several studies have shown that people with higher levels of toxic substances in their blood—such as from the PCBs found in fish fat—are at increased risk of type 2 diabetes, though a cause-and-effect relationship hasn't been proved. (Toxic substances and vitamin D have also been implicated in type 1 diabetes, but the disease mechanism may be unrelated to what's going on in type 2.)
There are other factors that also fall into the category of environmental (as opposed to genetic) causes of diabetes. Certain injuries to the pancreas, from physical trauma or from drugs, can harm beta cells, leading to diabetes. Studies have also found that people who live in polluted areas are prone to type 2, perhaps because of inflammation. And an alternate theory of insulin resistance places the blame on damage caused by inflammation. Age also factors into type 2; beta cells can wear out over time and become less capable of producing enough insulin to overcome insulin resistance, which is why older people are at greater risk of type 2.
There is evidence that certain emotions can promote type 2 diabetes. A recent study found that depression seems to predispose people to diabetes. Other research has tied emotional stress to diabetes, though the link hasn't been proved. Researchers speculate that the emotional connection may have to do with the hormone cortisol, which floods the body during periods of stress. Cortisol sends glucose to the blood, where it can fuel a fight-or-flight response, but overuse of this system may lead to dysfunction.
Progression toward type 2 diabetes may even be self-perpetuating. Once a person begins to become insulin resistant, for whatever reason, things may snowball from there. The increased levels of circulating insulin required to compensate for resistance encourage the body to pack on pounds. That extra weight will in turn make the body more insulin resistant. Furthermore, the heavier a person is, the more difficult it can be to exercise, continuing the slide toward diabetes.
Finally, modern society should probably shoulder at least some of the blame for the type 2 diabetes epidemic. Access to cheap, calorie-laden foods may even influence type 2 risk beyond simply their effects on body weight; the stuff that is in processed foods, like high-fructose corn syrup, could alter the body's chemistry or gut microbes in a way that affects health. Add to that the fact that most Americans are sedentary, spending their time sitting in cubicles, driving in cars, playing video games, or watching television. The lack of exercise, plus the abundance of unhealthy foods, cultivates a fertile breeding ground for diabetes.
With type 1, a disease that often seems to strike suddenly and unexpectedly, the effects of environment and lifestyle are far less clear. But several theories attempt to explain why cases of type 1 have increased so dramatically in recent decades, by around 5 percent per year since 1980. The three main suspects now are too little sun, too good hygiene, and too much cow's milk.
In the sunshine, molecules in the skin are converted to vitamin D. But people stay indoors more these days, which could lead to vitamin D deficiency. Research shows that if mice are deprived of vitamin D, they are more likely to become diabetic. In people, observational studies have also found a correlation between D deficiency and type 1. "If you don't have enough D, then [your immune system] doesn't function like it should," says Chantal Mathieu, MD, PhD, a professor of experimental medicine and endocrinology at Katholieke Universiteit Leuven in Belgium. "Vitamin D is not the cause of type 1 diabetes. [But] if you already have a risk, you don't want to have vitamin D deficiency on board because that's going to be one of the little pushes that pushes you in the wrong direction."
A second theory, dubbed the hygiene hypothesis, blames the rise of type 1 on a society that's too clean. Good housekeeping and hygiene habits mean far fewer interactions with germs, which in turn may foster an immune system prone to going awry. "In a developing country, you have more infectious disease. This is associated with a lower risk of type 1 diabetes," says Li Wen, MD, PhD, an immunologist at the Yale University School of Medicine. In her lab, rodents raised in hyper-clean environments are more likely to get type 1 than those reared in dirtier cages.
A third notion is that changes in how babies are fed may be stoking the spread of type 1. In the 1980s, researchers noticed a decreased risk of type 1 in children who had been breast-fed. This could mean that there is a component of breast milk that is particularly protective for diabetes. But it has also led to a hypothesis that proteins in cow's milk, a component of infant formula, somehow aggravate the immune system and cause type 1 in genetically susceptible people. If true, it might be possible to remove that risk by chopping those proteins up into little innocuous chunks through a process called hydrolyzation. A large-scale clinical trial, called TRIGR, is testing this hypothesis and scheduled for completion in 2017.
Another study, known as TEDDY, is attempting to tackle all the possible causes of type 1 diabetes simultaneously. Over 15 years, the research will meticulously track newborns with a genetic predisposition for type 1 diabetes to pinpoint which environmental factors may determine whether they develop the disease. The study is due to wind up in 2023.
While it's conceivable that scientists will isolate a single factor as causing type 1 and type 2, the much more likely outcome is that there is more than one cause. Each person seems to take a unique path in developing diabetes. Someday, doctors may be able to assess an individual's genetic risk for diabetes, allowing him or her to dodge the particular environmental factors that would trigger the disease. And perhaps if the baffling question of why a person gets diabetes can be put to rest, the answer will also offer a cure for the disease.